Lung cancer is an aggressive disease that, despite recent advances in treatment, continues to have a low long-term survival rate. Thus, it is significant that the National Lung Cancer Screening Trial (NLST) demonstrated a significant drop in lung cancer mortality (20% reduction) through early-detection low-dose computed tomography (CT) lung screening. Subsequently, low-dose CT lung screening programs have seen a steady growth nationwide in the United States. However, the NLST also demonstrated that most of the detected pulmonary nodules will be benign (e.g., 96.4% of positive screens in the NLST trial were benign). The inability to distinguish benign from malignant nodules solely using expert visual interpretation has resulted in inconsistent algorithms. These algorithms frequently require repeated CT exams until (i) the lesion is of a size amenable to biopsy, (ii) a cancerous etiology becomes undoubtedly apparent radiographically, or (iii) two-year stability has been achieved suggesting benign entity. There are several shortcomings to the current diagnostic approach including: (i) high cost in diagnostic workup; (ii) repetitive radiation exposures for predominantly benign lesions; (iii) invasive procedures with occasional complications; and (iv) prolonged angst by patients awaiting a definitive diagnosis. Accordingly, improved methods to non-invasively differentiate between benign and malignant nodules are desired. Additionally, methods to non-invasive discriminate between primary or metastatic lesions and between lesions with and without genetic mutations are also desired. That is NLST illustrates that early detection and treatment is the key to improving long term survival, and improved methods of detection and discrimination can enable better informed and more personalized treatment, which is likely to also positively impact long term survival rates while decreasing costs, including emotional, physical, resources, or monetary costs.